The striatum is the main entrance of extrinsic information to the basal ganglia circuitry. It is largely made up of medium sized GABAergic neurons characterized by densely spiny dendritic trees, the so- called medium spiny neurons (MSNs). The cerebral cortex and the thalamus are the two main sources of excitatory glutamatergic afferents to MSNs. Midbrain dopaminergic inputs tightly regulate striatal glutamatergic neurotransmission. Lesion of the nigrostriatal dopaminergic system in animal models of Parkinson's disease (PD) results in a dramatic loss of dendritic spines accompanied with altered transmission and plasticity of corticostriatal synapses. During the past funding period, we characterized in detail the synaptic connectivity of striatal glutamatergic afferents in nonhuman primates using the vesicular glutamate transporters 1 and 2 (vGluT1 and vGluT2) as specific markers of corticostriatal and thalamostriatal systems, respectively. Our data also provided further evidence for a major loss of dendritic spines and a relative increase in vGluT1 immunoreactivity in the striatum of MPTP-treated parkinsonian monkeys, thereby extending previous evidence for alterations in corticostriatal transmission in Parkinsonism. During the next funding period, we propose to extend these recent findings and further investigate plastic changes in spine morphology and AMPA glutamate receptor subunits localization that could possibly underlie functional alterations in corticostriatal and thalamostriatal glutamatergic transmission in Parkinsonism. These anatomical studies will be complemented with an in vivo assessment of changes in the physiological responses of striatal MSNs to activation of the corticostriatal system in awake MPTP-treated parkinsonian monkeys. Our proposal aims at achieving the following three goals: (1) To characterize the morphology and ultrastructural features of dendritic spines that receive cortical and thalamic inputs in the striatum of normal and parkinsonian monkeys, (2) To characterize and compare the subcellular and subsynaptic localization of the AMPA GluR1 subunit in spines contacted by cortical or thalamic inputs in normal and MPTP-treated parkinsonian monkeys and (3) To compare the electrophysiological effects of cortical stimulation upon striatal projection neurons activation between normal and parkinsonian monkeys, and determine if dopaminergic antiparkinsonian therapy mediates its beneficial effect through regulation of corticostriatal glutamatergic transmission . Together, these studies will provide highly significant information that will help further understand the physiology, pathophysiology and structural plasticity of the two main glutamatergic systems that regulate striatofugal neurons activity under normal and parkinsonian conditions. PUBLIC HEALTH RELEVANCE: The main goal of this proposal is to characterize morphological, neurochemical and electrophysiological changes induced in the excitatory glutamatergic transmission from the cerebral cortex and the thalamus onto the basal ganglia circuitry in Parkinson's disease. To achieve this endeavor, we will use high resolution anatomical techniques at the electron microscopic level combined with in vivo electrophysiological recording methods in an awake non-human primate model of Parkinson's disease. The results of these studies should further our current understanding of the neural plasticity that underlies functional changes in the basal ganglia circuitry in the parkinsonian state.